The long-term objectives of this project are to determine the role of complement in the generation of antigen-specific immune responses and to understand how complement deficiency leads to the loss of tolerance and the development of autoimmune diseases such as systemic lupus erythematosus. Defects in the ability to mount specific antibody responses to naive protein antigens are found with genetic deficiencies of complement proteins and in experimental animals rendered complement deficient or treated with antibodies which downregulate the membrane expression of receptors (CR) for complement proteins. Recently, we have also identified defective antigen- specific Th cell responses in mice rendered complement deficient. Therefore, the specific aims are to elucidate the mechanism(s) of antigen- specific T and B cell unresponsiveness in mice following complement depletion and complement receptor downregulation by: 1) determining how the trafficking and targeting of antigen is altered in these mice; 2) analysis of the potential role of APC dysfunction in complement deficient and anti- CR mAb treated mice; and 3) examination of the nature of the antigen- specific T cell unresponsiveness. To further elucidate the mechanisms of the effects of complement deficiency and anti-CR1/CR2 antibody treatment on antigen specific immune responses, we are using the well characterized hen egg lysozyme (HEL) lAk restricted immune response. Using this murine model we have observed that complement deficient animals exhibit not only a diminished HEL-specific antibody response but fail to generate HEL-reactive T cells. Using the HEL model and anti-HEL antibody transgenic mice, we propose to investigate how complement deficiency and anti-CR1/CR2 mAb treatment may lead to antigen specific unresponsiveness by examining the effect of complement blockade on the processing, trafficking and presentation of antigen in addition to subsequent B and T cell interactions. The proposed research in this application will make significant contributions to understanding the basic question of the role of complement in the generation and regulation of antigen specific B and T cell responses to naive antigens. Additionally, this investigation is highly relevant to the investigation of rheumatic diseases, as many diseases characterized by autoimmunity occur in individuals with genetic complete deficiencies of early components.